Alzheimer's Disease (AD) is the most common dementing illness and afflicts over 5 million people in the USA currently, with an annual health care burden near $ 200 billion (Alzheimer's Association, 2012, Alzheimer's Dement 8:131-168). Unfortunately, no current therapy modifies the course of AD. The clinical dementia of AD is coupled with a distinct pathology, with senile plaques consisting of amyloid-β (Aβ) peptide, and with neurofibrillary tangles consisting of hyperphosphorylated Tau protein. The existence of rare autosomal dominant cases of AD caused by mutations of the amyloid-β precursor protein (APP) or the presenilin (PS1 and PS2) processing enzymes that produce Aβ provides genetic proof that APP/Aβ pathways can trigger clinical AD (Hardy et al., 2002, Science 297:353-356; Tanzi et al, 2005, Cell 120:545-555; Holtzman et al., 2011, Science Transl Med 3:77sr71; Lu et al., 1997, J Neurosci 17:5196-5205). Other APP mutations reduce AD risk (Jonsson et al., 2012, Nature 488:96-99). Tau mutations cause dementia in frontotemporal lobar degeneration (Mackenzie et al., 2010, Acta Neuropathol 119:1-4).
Biomarker studies of late onset non-familial AD span the progression of disease from presymptomatic stage, to mild cognitive impairment, to AD (Holtzman et al., 2011, Science Transl Med 3:77sr71; Shaw et al., 2009, Ann Neurol 65:403-413; Jack et al., 2010, Lancet Neurol 9:119-128). Such observations have revealed that Aβ dysregulation, as detected by CSF levels or by positron emission tomography, is the earliest detectable change of the AD process, consistent with Aβ serving as the trigger for the disease.
Large extracellular and inert plaques of amyloid mark the pathology, but attention has focused on conformationally distinct soluble oligomers of Aβ (Aβo) as being neurotoxic (Lesne et al., 2006, Nature 440:352-357; Shankar et al., 2008, Nat Med 14:837-842; Walsh et al., 2002, Nature 416:535-539; Lambert et al., 1998, Proc Natl Acad Sci USA 95:6448-6453). Specifically, neurotoxicity is characterized by synaptic malfunction, and is accompanied by loss of dendritic spines. Chronically, synaptic changes are followed by neurofibrillary tangles, neuro-inflammation, and neuronal cell loss.
In the only reported genome-wide unbiased screen for Aβo binding sites, cellular prion protein (PrPC) was identified (Lauren et al., 2009, Nature 457:1128-1132). Aβ binds with high affinity to PrPC and is oligomer specific, with little or no affinity for fibrillary or monomeric states (Lauren et al., 2009, Nature 457:1128-1132; Chen et al., 2010, J Biol Chem 285:26377-26383; Calella et al., 2010, EMBO Mol Med 2:306-314; Balducci et al., 2010, Proc Natl Acad Sci USA 107:2295-2300). In vivo, PrPC is not essential for certain Aβ-related phenotypes (Calella et al., 2010, EMBO Mol Med 2:306-314; Balducci et al., 2010, Proc Natl Acad Sci USA 107:2295-2300; Kessels et al., 2010, Nature 466:E3-4: discussion E4-5; Cisse et al., 2011, J Neurosci 31:10427-10431), but is required for cell death in vitro, for reduced survival of APP/PS1 transgenic lines, for epileptiform discharges, for synapse loss, for serotonin axon degeneration and for spatial learning and memory deficits (Um et al., 2012, Nat Neurosci 15:1227-1235; Resenberger et al., 2011, EMBO J. 30:2057-2070; Bate et al., 2011, J Biol Chem 286:37955-37963; Alier et al., 2011, J Neurosci 31:16292-16297; Chung et al, 2010, BMC Neurosci 11:130; Gimbel et al., 2010, J Neurosci 30:6367-6374; Kudo et al., 2012; Hum Mol Genet. 21:1138-1144; You et al., 2012, Proc Natl Acad Sci USA 109:1737-1742). Critically, the ability of human AD brain-derived Aβ species to suppress hippocampal synaptic plasticity requires PrPC, and human AD contains PrPC-interacting Aβo species and Aβ-PrPC complexes (Um et al., 2012, Nat Neurosci 15:1227-1235; Zou et al., 2011, J Biol Chem 286:15095-15105; Freir et al., 2011, Nat Commun 2:336; Barry et al., 2011, J Neurosci 31:7259-7263).
Despite the enormous and growing burden of AD, there remains no effective disease-modifying therapy today. The approaches now in clinical trials are mostly centered on efforts to alter Aβ itself (e.g., its production or clearance or aggregation). No major trial has centered on the signal transduction downstream of toxic Aβ species. In fact, there has been no successful clinical trial targeting Tau and/or Tau kinases in AD to this date.
There are nine members of Src family of intracellular non-receptor tyrosine kinases. Five of them (Src, Fyn, Lck, Lyn, and Yes) are expressed in the central nervous system, but Src and Fyn are most highly expressed in the brain. Fyn activity, like that of other Src family kinases, is regulated by intramolecular interactions that depend on an equilibrium between tyrosine phosphorylation and dephosphorylation (Thomas et al., 1997, Ann. Rev. Cell & Dev. Biol. 13:513-609). In the basal state, catalytic activity is constrained by intramolecular interactions, such as engagement of the SH2 domain by a phosphorylated C-terminal Tyr 527. Disruption of these interactions by phosphorylation at Tyr 416 in the activation loop of the kinase domain and/or by dephosphorylation of Tyr 527 results in Fyn activation (Hunter, 1987, Cell, 49: 1-4).
Fyn has been localized to the post-synaptic density (PSD) fraction of the brain and amongst its substrates are receptors for the major excitatory transmitter glutamate. Fyn regulates glutamate receptor trafficking and synaptic plasticity (Nakazawa et al., 2001, J Biol Chem 276:693-699; Kojima et al., 1998, Learning & Memory (Cold Spring Harbor N.Y.) 5:429-445; Grant et al., 1992, Science 258:1903-1910; Prybylowski et al., 2005, Neuron 47:845-857). Specifically, Fyn phosphorylates the NMDA-type glutamate receptor subunits, NR2A and NR2B (Suzuki et al., 1995, Biochem Biophys Res Commun 216:582-588).
There remains an unmet need in the art for novel methods of treating an Aβ-modulated disease or disorder, such as AD, and/or improving cognition in a subject. The present invention satisfies these unmet needs.